The invention relates to a series of N-heterocyclic compounds and derivatives useful as inhibitors of nitric oxide synthase (NOS) and to methods of therapy for various diseases employing those compounds.
Nitrogen monoxide (NO) has been implicated in a number of diverse physiological processes, including smooth muscle relaxation, platelet inhibition, nerve transmission, immune regulation and penile erection. Nitric oxide is produced under various conditions by virtually all nucleated mammalian cells. A number of pathologies are ascribed to abnormalities in NO production including stroke, insulin dependent diabetes, septic shock-induced hypotension, rheumatoid arthritis and multiple sclerosis. Nitric oxide is synthesized in biological tissues by an enzyme called nitric oxide synthase (NOS) which uses NADPH and molecular oxygen to oxidize L-arginine to citrulline and nitric oxide.
Nitric oxide synthase (NOS) exists in at least three isoforms, which fall into two primary categories: constitutive and inducible. Two constitutive isoforms, which are calcium and calmodulin dependent, have been identified, and one inducible isoform has been identified. The constitutive isoforms are (1) a neuronal isoform, NOS-1 or nNOS, which is found in the brain and skeletal muscles and (2) an endothelial isoform, NOS-3 or eNOS, which is expressed in the endothelium of blood vessels, the epithelium of the bronchial tree and in the brain. These constitutive isoforms are not the target of the NOS inhibitors of the present invention.
The inducible isoform (NOS2 or iNOS) is expressed in virtually all nucleated mammalian cells following exposure to inflammatory cytokines or lipopolysaccharide. Its presence in macrophages and lung epithelial cells is particularly noteworthy. The inducible isoform is neither stimulated by calcium nor blocked by calmodulin antagonists. It contains several tightly bound co-factors, including FMN, FAD and tetrahydrobiopterin.
Nitric oxide generated by the inducible form of NOS has been implicated in the pathogenesis of inflammatory diseases. In experimental animals, hypotension induced by lipopolysaccharide or tumor necrosis factor xcex1 can be reversed by NOS inhibitors. Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis and interleukin therapy in cancer patients. It is expected that an iNOS inhibitor would be effective in treating cytokine-induced hypotension. In addition, recent studies have suggested a role for NO in the pathogenesis of inflammation, and NOS inhibitors would therefore have beneficial effects on inflammatory bowel disease, cerebral ischemia and arthritis. Inhibitors of NOS may also be useful in treating adult respiratory distress syndrome (ARDS) and myocarditis, and they may be useful as adjuvants to short term immunosuppression in transplant therapy.
The diversity and ubiquity of NO function in physiology make the specific therapeutic targeting of NO-related phenomena an important consideration. Since endogenous NO production is the result of the actions of related but distinct isozymes, the differential inhibition of NOS isozymes allows more selective therapy with fewer side effects.
In one aspect, the invention is directed compounds of formula (I): 
wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
each X, Y and Z are independently N or C(R19);
each U is N or G(R5), provided that U is N only when X is N and Z and Y are CR19;
V is N(R4), S, O or C(R4)H;
each W is N or CH;
Q is chosen from the group consisting of a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94R1)xe2x80x94, xe2x80x94S(O)t, and xe2x80x94N(R6)xe2x80x94;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero; when A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)1R1 (where t is zero), or xe2x80x94N(R1)SO2R22, n, q, and r cannot all be zero; and when Q is a heteroatom and A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero) or xe2x80x94N(R1)SO2R22, m and n cannot both be zero;
t is zero, one or two;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]xe2x80x94R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, xe2x80x94[C1-C8 alkyl]xe2x80x94C(O)N(R1)R2, xe2x80x94[C1-C8 alkyl]xe2x80x94N(R1)R2, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is xe2x80x94N(R6)xe2x80x94 or a direct bond to R3, R3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and xe2x80x94C(xe2x95x90NR18)xe2x80x94NH2;
or xe2x80x94Qxe2x80x94R3 taken together represents xe2x80x94C(O)OH, xe2x80x94C(O)N(R1)R2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R1)R2 or 
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl, provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
R6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, acyl, xe2x80x94C(O)R8, xe2x80x94C(O)xe2x80x94[C1-C8 alkyl]-R8, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, xe2x80x94C(xe2x95x90NH)xe2x80x94N(CN)R1, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)C(O)xe2x80x94R23xe2x80x94N(R1)R2, and xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R23xe2x80x94C(O)OR1;
each R8 and R9 are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14, R15, R17, and R20 is independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R18 is hydrogen, NO2, or toluenesulfonyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R23 is an amino acid residue;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (II): 
wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
each X, Y and Z are independently N or C(R19);
each U is N or C(R5), provided that U is N only when X is N and Z and Y are CR19;
each W is N or CH;
n is zero or an integer from 1 to 3;
t is zero, one or two; 
is an optionally substituted N-heterocyclyl;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]-R11 (optionally substituted by hydroxy), optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
each R9 is independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R14 and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl; and
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (III): 
wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
each X, Y and Z are independently N or C(R19);
each U is N or C(R5), provided that U is N only when X is N and Z and Y are CR19;
V is N(R4), S, O or C(R4)H;
each W is N or CH;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one;
t is zero, one or two; 
is an optionally substituted carbocyclyl or optionally substituted N-heterocyclyl;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]-R11 optionally substituted by hydroxy), optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl; provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
each R9 is independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14 and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl; and
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (Ya), formula (Yb) and formula (Yc): 
wherein:
n and m are each independently an integer from 1 to 4;
A is xe2x80x94C(O)OR1 or xe2x80x94C(O)N(R1)R2;
each W is N or CH;
each R1 is independently hydrogen, alkyl, aryl or aralkyl;
each R2 is independently hydrogen, C0-C20 alkyl, xe2x80x94(CH2)nxe2x80x94N(R1)2, heterocyclylalkyl (optionally substituted by alkyl, halo, haloalkyl or alkoxy), aralkyl (optionally substituted by halo, alkyl, alkoxy, or xe2x80x94N(R1)2);
R4 is hydroxy, cyano, heterocyclyl, xe2x80x94N(R1)R2, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94R1, xe2x80x94N(R1)xe2x80x94C(O)OR1, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94R1, or xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94N(R1)2;
R5 is hydrogen, halo, alkyl, aryl, aralkyl, or haloalkyl; and
t is zero, one or two;
as a single stereoisomer or mixture thereto, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (IV): 
wherein:
AA is an amino acid;
X, Y and Z are independently N or C(R19);
U is N or C(R5), provided that U is N only when X is N and Z and Y are CR19;
W is N or CH;
R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]xe2x80x94R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R5 is chosen from the group consisting of hydrogen, halo, alkyl haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
each R9 is independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R19 is hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they ate attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
t is zero, one or two;
as a single isomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (Va), formula (Vb) and formula (Vc): 
wherein B is a fused 5- or 6-membered optionally substituted carbocyclyl or heterocyclyl; and wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
each X and Y are independently N or C(R19);
V is N(R4), S, O or C(R4)H;
each W is N or CH;
Q is chosen from the group consisting of a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94R1)xe2x80x94, xe2x80x94S(O)t, and xe2x80x94N(R6)xe2x80x94;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero; when A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero), or xe2x80x94N(R1)SO2R22, n, q, and r cannot all be zero; and when Q is a heteroatom and A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero) or xe2x80x94N(R1)SO2R22, m and n cannot both be zero;
t is zero, one or two; 
is an optionally substituted N-heterocyclyl; 
is an optionally substituted carbocyclyl or optionally substituted N-heterocyclyl;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]xe2x80x94R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, xe2x80x94[C1-C8 alkyl]xe2x80x94C(O)N(R1)R2, xe2x80x94[C1-C8 alkyl]xe2x80x94N(R1)R2, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is xe2x80x94N(R6)xe2x80x94 or a direct bond to R3, R3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and xe2x80x94C(xe2x95x90NR18)xe2x80x94NH2; or xe2x80x94Qxe2x80x94R3 taken together represents xe2x80x94C(O)OH, xe2x80x94C(O)N(R1)R2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R1)R2 or 
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl;
provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, acyl, xe2x80x94C(O)R8, xe2x80x94C(O)xe2x80x94[C1-C8 alkyl]-R8, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, xe2x80x94C(xe2x95x90NH)xe2x80x94N(CN)R1, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)C(O)xe2x80x94R23xe2x80x94N(R1)R2, and xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R23xe2x80x94C(O)OR1;
each R8 and R9 are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)tR22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14, R15, R17, and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R18 is hydrogen, NO2, or toluenesulfonyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R23 is an amino acid residue;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (VIa), formula (VIb) or formula (VIc): 
wherein B is a fused 5- or 6-membered optionally substituted carbocyclyl or heterocyclyl; and wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
each X and Z are independently N or C(R19);
V is N(R4, S, O or C(R4)H;
each W is N or CH;
Q is chosen from the group consisting of a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94R1)xe2x80x94, xe2x80x94S(O)t, and xe2x80x94N(R6)xe2x80x94;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero; when A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero), or xe2x80x94N(R1)SO2R22, n, q, and r cannot all be zero; and when Q is a heteroatom and A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero) or xe2x80x94N(R1)SO2R22, m and n cannot both be zero;
t is zero, one or two; 
is an optionally substituted N-heterocyclyl; 
is an optionally substituted carbocyclyl or optionally substituted N-heterocyclyl;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]-R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, xe2x80x94[C1-C8 alkyl]xe2x80x94C(O)N(R1)R2, xe2x80x94[C1-C8 alkyl]xe2x80x94N(R1)R2, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is xe2x80x94N(R6)xe2x80x94 or a direct bond to R3, R3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and xe2x80x94C(xe2x95x90NR18)xe2x80x94NH2;
or xe2x80x94Qxe2x80x94R3 taken together represents xe2x80x94C(O)OH, xe2x80x94C(O)N(R1)R2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R1)R2 or 
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl;
provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, xe2x80x94[C1-C8 alkyl]-R5, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, acyl, xe2x80x94C(O)R8, xe2x80x94C(O)xe2x80x94[C1-C8 alkyl]-R8, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, xe2x80x94C(xe2x95x90NH)xe2x80x94N(CN)R1, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R23xe2x80x94C(O)OR1;
each R8 and R9 are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14, R15, R17, and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R18 is hydrogen, NO2, or toluenesulfonyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R23 is an amino acid residue;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (VIIa), formula (VIIb), or formula (VIIc): 
wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
each X, Y and Z are independently N or C(R19);
each U is N or C(R5), provided that U is N only when X is N and Z and Y are CR19;
V is N(R4), S, O or C(R4)H;
each W is N or CH;
Q is chosen from the group consisting of a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94R1)xe2x80x94, xe2x80x94S(O)t, and xe2x80x94N(R6)xe2x80x94;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero; when A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero), or xe2x80x94N(R1)SO2R22, n, q, and r cannot all be zero; and when Q is a heteroatom and A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (when t is zero) or xe2x80x94N(R1)SO2R22, m and n cannot both be zero;
t is zero, one or two; 
is an optionally substituted N-heterocyclyl; 
is an optionally substituted carbocyclyl or optionally substituted N-heterocyclyl;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]-R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, xe2x80x94[C1-C8 alkyl]xe2x80x94C(O)N(R1)R2, xe2x80x94[C1-C8 alkyl]xe2x80x94N(R1)R2, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is xe2x80x94N(R6)xe2x80x94 or a direct bond to R3, R3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and xe2x80x94C(xe2x95x90NR18)xe2x80x94NH2;
or xe2x80x94Qxe2x80x94R3 taken together represents xe2x80x94C(O)OH, xe2x80x94C(O)N(R1)R2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R1)R2 or 
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl;
provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
R6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, acyl, xe2x80x94C(O)R8, xe2x80x94C(O)xe2x80x94[C1-C8 alkyl]-R8, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, xe2x80x94C(xe2x95x90NH)xe2x80x94N(CN)R1, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)C(O)xe2x80x94R23xe2x80x94N(R1)R2, and xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R23xe2x80x94C(O)OR1;
each R8 and R9 are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)tR22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14, R15, R17, and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R18 is hydrogen, NO2, or toluenesulfonyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R23 is an amino acid residue;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to compounds of formula (VIII): 
wherein two of X, Y and Z are nitrogen and the third is CH.
In another aspect, the invention provides compounds of formula (IXa), formula (IXb), or formula (IXc): 
wherein: 
is a solid support;
L is a linker residue;
each X, Y and Z are independently N or C(R19);
each U is N or C(R5), provided that U is N only when X is N and Z and Y are CR19;
V is N(R4), S, O or C(R4)H;
each W is N or CH;
Q is chosen from the group consisting of a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94R1)xe2x80x94, xe2x80x94S(O)t, and xe2x80x94N(R6)xe2x80x94;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero;
t is zero, one or two; 
is an optionally substituted N-heterocyclyl; 
is an optionally substituted carbocyclyl or optionally substituted N-heterocyclyl;
each R2 is independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]xe2x80x94R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
R3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, xe2x80x94[C1-C8 alkyl]xe2x80x94C(O)N(R1)R2, xe2x80x94[C1-C8 alkyl]xe2x80x94N(R1)R2, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is xe2x80x94N(R6)xe2x80x94 or a direct bond to R3, R3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and xe2x80x94C(xe2x95x90NR18)xe2x80x94NH2;
or xe2x80x94Qxe2x80x94R3 taken together represents xe2x80x94C(O)OH, xe2x80x94C(O)N(R1)R2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R1)R2 or 
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl;
provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
R6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, acyl, xe2x80x94C(O)R6, xe2x80x94C(O)xe2x80x94[C1-C8 alkyl]-R6, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, xe2x80x94C(xe2x95x90NH)xe2x80x94N(CN)R1, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)C(O)xe2x80x94R23xe2x80x94N(R1)R2, and xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R23xe2x80x94C(O)OR1;
each R8 and R9 are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14, R15, R17, and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R18 is hydrogen, NO2, or toluenesulfonyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R23 is an amino acid residue;
as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to pharmaceutical compositions comprising a compound of formula (I), formula (II), formula (III), formula (IV), formula (Ya), formula (Yb), formula (Yc), formula (Va), formula (Vb), formula (Vc), formula (VIa), formula (VIb), formula (VIc), formula (VIIa), formula (VIIb), or formula (VIIc) as described above, and a pharmaceutically acceptable carrier.
In another aspect, the invention is directed to processes for synthesizing compounds of formula (I), formula (II) and formula (III) as described above: comprising the sequential steps of:
(a) reacting one equivalent of a compound of formula (XI): 
where W is N or CH;
with about one equivalent of an chloro-substituted compound of formula (XII): 
where X, Y and Z are independently N or C(R19);
U is N or C(R5), provided that U is N only when X is N and Z and Y are CR19, and provided that X, Y and Z can not all be C(R19) when U is C(R5);
R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, xe2x80x94OR16, xe2x80x94S(O)txe2x80x94R16, xe2x80x94N(R16)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94N(R16)C(O)OR16, xe2x80x94N(R16)C(O)R16, xe2x80x94[C0-C8 alkyl]-C(O)OR16, xe2x80x94[C0-C8 alkyl]xe2x80x94C(H)[C(O)OR16]2, and xe2x80x94[C0-C8 alkyl]xe2x80x94C(O)N(R1)R16;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl; and
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
to produce a compound of formula (XII): 
(b) reacting said compound of formula (XIII) with a compound of formula (XIVa), formula (XIVb), or formula (XIVc): 
wherein:
A is xe2x80x94R1, xe2x80x94OR1, xe2x80x94C(O)N(R1)R2, xe2x80x94P(O)[N(R1)R2]2,xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1, xe2x80x94SO2NHC(O)R1, xe2x80x94N(R1)SO2R22, xe2x80x94SO2N(R1)H, xe2x80x94C(O)NHSO2R22, or xe2x80x94CHxe2x95x90NOR1;
V is N(R4), S, or O;
Q is chosen from the group consisting of a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94R1)xe2x80x94, xe2x80x94S(O)t, and xe2x80x94N(R6)xe2x80x94;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero; when A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)1R1 (where t is zero), or xe2x80x94N(R1)SO2R22, n, q, and r cannot all be zero; and when Q is a heteroatom and A is xe2x80x94OR1, xe2x80x94N(R1)C(O)R2, xe2x80x94N(R16)C(O)OR2, xe2x80x94N(R1)R21, xe2x80x94N(R16)C(O)N(R1)R16, xe2x80x94S(O)tR1 (where t is zero) or xe2x80x94N(R1)SO2R22, m and n cannot both be zero;
t is zero, one or two; 
is an optionally substituted N-heterocyclyl; 
is an optionally substituted carbocyclyl or optionally substituted N-heterocyclyl;
each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, xe2x80x94[C0-C8 alkyl]-R9, xe2x80x94[C2-C8 alkenyl]-R9, xe2x80x94[C2-C8 alkynyl]-R9, xe2x80x94[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), xe2x80x94[C1-C8]-R11 (optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, xe2x80x94[C1-C8 alkyl]xe2x80x94C(O)N(R1)R2, xe2x80x94[C1-C8 alkyl]xe2x80x94N(R1)R2, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is xe2x80x94N(R6)xe2x80x94 or a direct bond to R3, R3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and xe2x80x94C(xe2x95x90NR18)xe2x80x94NH2;
or xe2x80x94Qxe2x80x94R3 taken together represents xe2x80x94C(O)OH, xe2x80x94C(O)N(R1)R2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R1)R2 or 
R4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl;
provided that when A is xe2x80x94R1 or xe2x80x94OR1, R4 cannot be hydrogen, and when V is CH, R4 may additionally be hydroxy;
R6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, xe2x80x94[C1-C8 alkyl]-R8, xe2x80x94[C2-C8 alkyl]-R10, xe2x80x94[C1-C8 alkyl]-R11, acyl, xe2x80x94C(O)R8, xe2x80x94C(O)xe2x80x94[C1-C8 alkyl]-R8, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, and arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, xe2x80x94C(xe2x95x90NH)xe2x80x94N(CN)R1, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94R23xe2x80x94N(R1)C(O)xe2x80x94R23xe2x80x94N(R1)R2, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R23xe2x80x94C(O)OR1;
each R8 and R9 are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted xe2x80x94S(O)txe2x80x94R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R12, R13, R14, R15, R17, and R20 are independently hydrogen or alkyl;
each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
R18 is hydrogen, NO2, or toluenesulfonyl;
each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94C(O)R22 or xe2x80x94SO2R22;
or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R23 is an amino acid residue;
to produce a compound of formula (I), formula (II) or formula (III) as described above.
In another aspect, the invention is directed to processes for synthesizing a compound of formula (I), formula (II) and formula (III) as described above; comprising photolytically cleaving the compound of formula (IXa), formula (IXb) or formula (IXc): 
wherein:
U, V, W, X, Y, Z, R2, R3, R12, R13, R14, R15, R17 and R20 are as defined above for compounds of formula (I), formula (II) or formula (III); 
is a solid support;
and L is a linker residue of formula (IX): 
wherein the unsatisfied valence on the right of the formula represents the point of attachment to the solid substrate and the unsatisfied valence on the left of the formula represents the point of attachment to the ligand;
to form the compound of formula (I), formula (II) and formula (III) as defined above.
In another aspect, the invention is directed to methods of treating a condition resulting from an abnormality in nitric oxide production which comprises administering to a mammal having a condition resulting from an abnormality in nitric oxide production a therapeutically effective amount of compound of formula (I), formula (II), formula (III), formula (IV), formula (Ya), formula (Yb), formula (Yc), formula (Va), formula (Vb), formula (Vc), formula (VIa), formula (VIb), formula (VIc), formula (VIIa), formula (VIIb), or formula (VIIc) as described above.